Amino-combretastatin derivative and use thereof

Abstract

An amino-combretastatin derivative, and in particular a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, or a hydrate of the pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, and an isomer thereof are provided. In general formula (I),R1 is selected from a C1-C3 alkyl or a C1-C3 haloalkyl, and R2 and R3 are respectively and independently selected from a C1-C6 alkyl, a C1-C6 haloalkyl or a C1-C6 alcohol group. The present invention also relates to the use of such compounds in the preparation of drugs for the treatment of diseases caused by abnormal neovascularization, and tubulin aggregation inhibitors.

1 . A compound of general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, a solvate of the pharmaceutically acceptable salt and an isomer thereof, wherein the general formula (I) is: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from a C1-C3 alkyl and a C1-C3 haloalkyl; 
         R 2  and R 3  are each independently selected from a C1-C6 alkyl, a C1-C6 haloalkyl and a C1-C6 alcohol group. 
       
     
     
         2 . The compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 1 , wherein:
 R 1  is selected from methyl, ethyl, difluoromethyl and trifluoroethyl;   R 2  and R 3  are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, propenyl and propynyl; more preferably, R 2 =R 3 ; even more preferably, R 2  and R 3  are simultaneously selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, propenyl and propynyl.   
     
     
         3 . The compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 1 , wherein the compound is:
 (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-ethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-methoxyphenyl) ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-butyl)amino)propionamide)-4-ethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-butyl)amino)propionamide)-4-methoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-ethyl)amino)propionamide)-4-ethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-trifluoroethoxyphenyl), (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-propyl)amino)propionamide)-4-difluoromethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-butyl)amino)propionamide)-4-trifluoroethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-n-butyl)amino)propionamide)-4-difluoromethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-hydroxyethyl)amino)propionamide)-4-ethoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(bis(2-hydroxyethyl)amino)propionamide)-4-methoxyphenyl)ethylene, (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(2,2-difluoroethylamino)propionamide)-4-ethoxyphenyl)ethylene or (Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(2,2-dimethoxyethylamino)propionamide)-4-ethoxyphenyl)ethylene.   
     
     
         4 . The compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 1 , wherein the pharmaceutically acceptable salt refers to a salt formed by one or more basic salt-forming groups and an acid, wherein the acid is an organic acid and/or an inorganic acid. 
     
     
         5 . A medicament or pharmaceutical composition prepared from the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt or the isomer thereof according to  claim 1 . 
     
     
         6 . The medicament or pharmaceutical composition according to  claim 5 , wherein the medicament or pharmaceutical composition is in a formulation for topical, enteral or parenteral administration. 
     
     
         7 . The medicament or pharmaceutical composition according to  claim 6 , wherein the medicament or pharmaceutical composition prepared from the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof is a tablet or a capsule. 
     
     
         8 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 1  in preparing a medicament for treating a disease caused by abnormal neovascularization. 
     
     
         9 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 1  in preparing a tubulin aggregation inhibitor. 
     
     
         10 . A medicament or pharmaceutical composition prepared from the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt or the isomer thereof according to  claim 2 . 
     
     
         11 . A medicament or pharmaceutical composition prepared from the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt or the isomer thereof according to  claim 3 . 
     
     
         12 . A medicament or pharmaceutical composition prepared from the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt or the isomer thereof according to  claim 4 . 
     
     
         13 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 2  in preparing a medicament for treating a disease caused by abnormal neovascularization. 
     
     
         14 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 3  in preparing a medicament for treating a disease caused by abnormal neovascularization. 
     
     
         15 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 4  in preparing a medicament for treating a disease caused by abnormal neovascularization. 
     
     
         16 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 2  in preparing a tubulin aggregation inhibitor. 
     
     
         17 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 3  in preparing a tubulin aggregation inhibitor. 
     
     
         18 . Use of the compound of general formula (I), the pharmaceutically acceptable salt thereof, the hydrate thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt and the isomer thereof according to  claim 4  in preparing a tubulin aggregation inhibitor.